The objectives of the proposed research are to identify novel genes contributing to nicotine metabolism and smoking cessation and to prospective smoking cessation. Nicotine metabolism is associated with the number of cigarettes smoked per day (CPD), how cigarettes are smoked (smoking topography), responsiveness to smoking cessation treatment, and with carcinogen activation and level. Addiction to nicotine remains the largest modifiable risk factor and contributes to 30% of mortality in the U.S., with 0.5 M individuals dying annually from smoking. We will identify genes associated with nicotine metabolism (pharmacokinetic (PK) genes) through analysis of existing and novel genotype data in samples with fixed dose nicotine metabolic rate (fixed dose NMR) data obtained through a clinical laboratory protocol. We will validate the novel PK genes using random dose NMR data obtained from treatment-seeking smokers, and will investigate whether variation at these novel PK genes influences prospective smoking cessation. These analyses will be the first to explicitly translate PK SNPs associated with the fixed dose NMR from individuals participating in a clinical laboratory protocol to the random dose NMR obtained from treatment-seeking smokers participating in a clinical trial sample, and then into multiple RCTs to investigate association wih prospective smoking cessation (overall and by pharmacotherapy). The number of Cohorts (10) and the number of individuals to be genotyped (3,784) represent the largest collection of informative studies and individuals to be genotyped to identify PK SNPs associated with nicotine metabolism and prospective smoking cessation. Enhanced knowledge of the genetic variation that influences nicotine metabolism and smoking cessation clinical trial outcomes will improve our understanding of metabolism, identify novel targets for the development of smoking cessation therapies, and help characterize PK gene variant effects on smoking behaviors, response to smoking cessation treatment and tobacco-attributable disease.